Overexpression of FOXS1 in gastric cancer cell lines inhibits proliferation, metastasis, and epithelial-mesenchymal transition of tumor through downregulating wnt/β-catenin pathway.

Expression of forkhead box (FOX) superfamily members has been shown to be decreased in cancer, which was linked to poor prognosis of patients. The aim of this study was to investigate the expression of a new FOX superfamily member, FOXS1, in gastric cancer, and the influence of FOXS1 overexpression on the tumorigenesis of gastric cancer cells. The underlying molecular mechanism was also investigated. FOXS1 expression levels were firstly measured in 15 paired gastric cancer and peritumor tissue using quantitative polymerase chain reaction or immunohistochemistry. Secondly, FOXS1 overexpression models were established in two gastric cancer cell lines (SNU-216 and AGS) and FOXS1 knockdown model was established in SNU-638 gastric cancer cell line. Markers for cell proliferation, metastasis, cell cycle status, and wnt/β-catenin pathway were evaluated. Influence of FOXS1 overexpression on tumorigenesis was further evaluated in xenograft model. Expression of FOXS1 was significantly decreased in gastric cancer tissue in both messenger RNA and protein levels, compared with peritumor tissue. Our results showed that compared to cell lines transfected with negative control, gastric cancer cell lines with FOXS1 overexpression showed suppressed cell proliferation, metastasis, and increased ratio of G0/G1 phase. Xenograft model also showed suppressed tumor growth in FOXS1 overexpression group. Epithelial-mesenchymal transition was also inhibited when FOXS1 was overexpressed, which was indicated by an increase of E-cadherin expression and decrease in vimentin expression. Further investigation showed that expression of β-catenin was decreased, together with decreased expression in downstream signaling factors, c-Myc and cyclin-D1 in FOXS1 overexpression cell lines. On the other hand, knockdown of FOXS1 showed opposite trends in the changes of those markers for cell proliferation, metastasis, cell cycle status, and wnt/β-catenin pathway, compared with FOXS1 overexpression. In conclusion, the present study showed that FOXS1 expression is downregulated in most GC cases in our cohort, and this loss of expression may promote cell proliferation and metastasis through upregulation of wnt/β-catenin pathway.

Lu Q ，Ma X ，Li Y ，Song W ，Zhang L ，Shu Y ，Wan B ... -  《-》

Forkhead Box S1 mediates epithelial-mesenchymal transition through the Wnt/β-catenin signaling pathway to regulate colorectal cancer progression.

Recent studies have shown that the fox family plays a vital role in tumorigenesis and progression. Forkhead Box S1 (FOXS1), as a newly identified subfamily of the FOX family, is overexpressed in certain types of malignant tumors and closely associated with patient's prognosis. However, the role and mechanism of the FOXS1 in colorectal cancer (CRC) remain unclear. FOXS1 level in CRC tissues and cell lines was analyzed by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry (IHC) was used to detect the relationship between FOXS1 expression and clinicopathological features in 136 patients in our unit. The expression of FOXS1 was knocked down in CRC cells using small interfering RNA (siRNA) technology. Cell proliferation was assessed by CCK8 assay, colony formation, and 5-Ethynyl-20-deoxyuridine (EdU) incorporation assay. Flow cytometry detected apoptosis and wound healing, and Transwell assays determined cell migration and invasion. Western blotting was used to detect the levels of proteins associated with the Wnt/β-catenin signaling pathway. Then, we used short hairpin RNA (shRNA) to knock down FOXS1 to see the effect of FOXS1 on the proliferation, migration, invasion, and metastasis of CRC cells in vivo. Finally, we investigated the impact of Wnt activator LiCl on the proliferation, migration, invasion, and metastasis of CRC cells after FOXS1 knockdown. Compared to those in normal groups, FOXS1 overexpressed in CRC tissues and CRC cells (P < 0.05). Upregulation of FOXS1 association with poor prognosis of CRC patients. si-FOXS1 induced apoptosis and inhibited proliferation, migration, invasion, the epithelial-mesenchymal transition (EMT), and the Wnt/β-catenin signaling pathway in vitro; sh-FOXS1 inhibited the volume and weight of subcutaneous xenografts and the number of lung metastases in vivo. LiCl, an activator of Wnt signaling, partially reversed the effect of FOXS1 overexpression on CRC cells. FOXS1 could function as an oncogene and promote CRC cell proliferation, migration, invasion and metastasis through the Wnt/βcatenin signaling pathway, FOXS1 may be a potential target for CRC treatment.

Zhang L ，Ren CF ，Yang Z ，Gong LB ，Wang C ，Feng M ，Guan WX ... -  《Journal of Translational Medicine》

EphA2 promotes epithelial-mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer cells.

Huang J ，Xiao D ，Li G ，Ma J ，Chen P ，Yuan W ，Hou F ，Ge J ，Zhong M ，Tang Y ，Xia X ，Chen Z ... -  《-》

FOXS1 is regulated by GLI1 and miR-125a-5p and promotes cell proliferation and EMT in gastric cancer.

Wang S ，Ran L ，Zhang W ，Leng X ，Wang K ，Liu G ，Song J ，Wang Y ，Zhang X ，Wang Y ，Zhang L ，Ma Y ，Liu K ，Li H ，Zhang W ，Qin G ，Song F ... -  《-》

Forkhead Box S1 inhibits the progression of lung squamous cell carcinoma cells by mediating Wnt/β-catenin pathway.

Wang F ，Li S 《CHINESE JOURNAL OF PHYSIOLOGY》